Design and characterisation of piperazine-benzofuran integrated dinitrobenzenesulfonamide as Mycobacterium tuberculosis H37Rv strain inhibitors.

Molecular hybridisation of four bioactive fragments piperazine, substituted-benzofuran, amino acids, and 2,4-dinitrobenzenesulfonamide as single molecular architecture was designed. A series of new hybrids were synthesised and subjected to evaluation for their inhibitory activity against Mycobacterium tuberculosis (Mtb) H37Rv. 4d-f and 4o found to exhibit MIC as 1.56 µg/mL, equally active as ethambutol whereas 4a, 4c, 4j displayed MIC 0.78 µg/mL were superior to ethambutol. Tested compounds demonstrated an excellent safety profile with very low toxicity, good selectivity index, and antioxidant properties. All the newly synthesised compounds were thoroughly characterised by analytical methods. The result was further supported by molecular modelling studies on the crystal structure of Mycobacterium tuberculosis enoyl reductase.

Spirocyclic sulfonamides with carbonic anhydrase inhibitory and anti-neuropathic pain activity.

A novel series of 4-oxo-spirochromane bearing primary sulfonamide group were synthetized as Carbonic Anhydrase inhibitors (CAIs) and tested for their management of neuropathic pain. Indeed, CAs have been recently validated as novel therapeutic targets in neuropathic pain. All compounds, here reported, showed strong activity against hCA II and hCA VII with KI values in the low or sub-nanomolar range. Two compounds (6d and 6l) showed good neuropathic pain attenuating effects and longer duration than drug reference acetazolamide in an animal model of oxaliplatin induced neuropathy.

Synthesis of novel benzenesulfamide derivatives with inhibitory activity against human cytosolic carbonic anhydrase I and II and Vibrio cholerae α- and ß-class enzymes.

The synthesis of a new series of sulfamides incorporating ortho-, meta, and para-benzenesulfamide moieties is reported, which were investigated for the inhibition of two human (h) isoforms of the zinc enzyme carbonic anhydrase (CA, EC 4.2.1.1), hCA I and II, and two Vibrio cholerae enzymes, belonging to the α- and ß-CA classes (VchCAα, VchCAß). The compounds were prepared by using the "tail approach", aiming to overcome the scarcity of selective inhibition profiles associated to CA inhibitors belonging to the zinc binders. The built structure-activity relationship showed that the incorporation of benzhydryl piperazine tails on a phenyl sulfamide scaffold determines rather good efficacies against hCA I and VchCAα, with several compounds showing KIs < 100 nM. The activity was lower against hCA II and VchCAß, probably due to the fact that the incorporated tails are quite bulky. The obtained evidences allow us to continue the investigations of different tails/zinc binding groups, with the purpose to increase the effectiveness/selectivity of such inhibitors against bacterial CAs from pathogens, affording thus potential new anti-infectives.

Novel Sulfamide-Containing Compounds as Selective Carbonic Anhydrase I Inhibitors.

The development of isoform selective inhibitors of the carbonic anhydrase (CA; EC 4.2.1.1) enzymes represents the key approach for the successful development of druggable small molecules. Herein we report a series of new benzenesulfamide derivatives (-NH-SO2NH2) bearing the 1-benzhydrylpiperazine tail and connected by means of a ß-alanyl or nipecotyl spacer. All compounds 6a-l were investigated in vitro for their ability to inhibit the physiological relevant human (h) CA isoforms such as I, II, IV and IX. Molecular modeling provided further structural support to enzyme inhibition data and structure-activity relationship. In conclusion the hCA I resulted the most inhibited isoform, whereas all the remaining ones showed different inhibition profiles.

Synthesis and characterization of a disubstituted piperazine derivative with T-type channel blocking action and analgesic properties.

BACKGROUND: T-type calcium channels are important contributors to signaling in the primary afferent pain pathway and are thus important targets for the development of analgesics. It has been previously reported that certain piperazine-based compounds such as flunarizine are able to inhibit T-type calcium channels. Thus, we hypothesized that novel piperazine compounds could potentially act as analgesics. RESULTS: Here, we have created a series of 14 compound derivatives around a diphenyl methyl-piperazine core pharmacophore. Testing their effects on transiently expressed Cav3.2 calcium channels revealed one derivative (3-((4-(bis(4-fluorophenyl)methyl)piperazin-1-yl)methyl)-4-(2-methoxyphenyl)-1,2,5-oxadiazole 2-oxide, compound 10e) as a potent blocker. 10e mediate tonic block of these channels with an IC50 of around 4 micromolar. 10e also blocked Cav3.1 and Cav3.3 channels, but only weakly affected high-voltage-activated Cav1.2 and Cav2.2 channels. Intrathecal delivery of 10e mediated relief from formalin and complete Freund's adjuvant induced inflammatory pain that was ablated by genetic knockout of Cav3.2 channels. CONCLUSIONS: Altogether, our data identify a novel T-type calcium channel blocker with tight structure activity relationship (SAR) and relevant in vivo efficacy in inflammatory pain conditions.

Furazan and furoxan sulfonamides are strong α-carbonic anhydrase inhibitors and potential antiglaucoma agents.

A series of furazan and furoxan sulfonamides were prepared and studied for their ability to inhibit human carbonic anhydrase (CA, EC 4.2.1.1) isoforms hCA I, hCA II, hCA IX, and hCA XII. The simple methyl substituted products 3-5 were potent inhibitors. Differing structural modifications of these leads had differing effects on potency and selectivity. In particular, products in which the sulfonamide group is separated from the hetero ring by a phenylene bridge retained high potency only on the hCA XII isoform. The sulfonamides 3-5 exerted intraocular pressure (IOP) lowering effects in vivo in hypertensive rabbits more efficiently than dorzolamide. Some other products (39-42), although less effective in vitro hCA II/XII inhibitors, also effectively lowered IOP in two different animal models of glaucoma.

Synthesis, Characterization, In Silico DFT, Molecular Docking, and Dynamics Simulation Studies of Phenylhydrazono Phenoxyquinolones for Their Hypoglycemic Efficacy.

A series of novel 24 phenylhydrazono phenoxyquinoline derivatives were synthesized with moderate to excellent yield and screened for their efficacy against the α-amylase enzyme through in silico studies. The structures were characterized using spectroscopic techniques such as 1HNMR, 13CNMR, and HREI-MS. Comprehensive computational studies including, drug-likeness and ADMET profiling, quantum chemical calculations, molecular docking, and molecular dynamics (MD) simulation studies, were performed. A density functional theory study of the synthesized compounds indicated a favorable reactivity profile. The synthesized novel analogues were docked against α-amylase (PDB 6OCN) enzymes to investigate the binding interactions. Based on the docking studies, one of the compounds was found to be the hit with the highest negative binding affinity for α-amylase. A MD simulation study indicated stable binding throughout the simulation.

High-throughput computational screening for identification of potential hits against bacterial Acriflavine resistance protein B (AcrB) efflux pump.

Antibiotic resistance is a pressing global health challenge, driven in part by the remarkable efflux capabilities of efflux pump in AcrB (Acriflavine Resistance Protein B) protein in Gram-negative bacteria. In this study, a multi-approached computational screening strategy encompassing molecular docking, In silico absorption, distribution, metabolism, excretion and toxicity (ADMET) analysis, druglikeness assessment, molecular dynamics simulations and density functional theory studies was employed to identify novel hits capable of acting against AcrB-mediated antibiotic resistance. Ligand library was acquired from the COCONUT database. Performed computational analyses unveiled four promising hit molecules (CNP0298667, CNP0399927, CNP0321542 and CNP0269513). Notably, CNP0298667 exhibited the highest negative binding affinity of -11.5 kcal/mol, indicating a possibility of strong potential to disrupt AcrB function. Importantly, all four hits met stringent druglikeness criteria and demonstrated favorable in silico ADMET profiles, underscoring their potential for further development. MD simulations over 100 ns revealed that the CNP0321542-4DX5 and CNP0269513-4DX5 complexes formed robust and stable interactions with the AcrB efflux pump. The identified hits represent a promising starting point for the design and optimization of novel therapeutics aimed at combating AcrB-mediated antibiotic resistance in Gram-negative bacteria.Communicated by Ramaswamy H. Sarma.

Novel 2,4-Dichloro-5-sulfamoylbenzoic Acid Oxime Esters: First Studies as Potential Human Carbonic Anhydrase Inhibitors.

In this study, a focused library of oxime ester derivatives of 2,4-dichloro-5-sulfamoylbenzoic acid (lasamide) containing Schiff bases was synthesized and tested in vitro for their ability to inhibit the cytosolic human carbonic anhydrases (hCAs) I and II, as well as the transmembrane and tumor-associated IX and XII isoforms. As a result, we obtained a first line of knowledge on lasamide derivatives potentially useful for development as CA inhibitors (CAIs). In particular, we focused our attention on the derivative 11, which was selective toward hCAs IX and XII over the cytosolic isoenzymes. An in silico study was conducted to assess the binding mode of 11 within hCAs IX and XII. Also, antiproliferative assays highlighted promising derivatives. The data obtained in this study are currently in use for the development of better-performing compounds on the tumor-associated isoforms.

Identification of potential biogenic chalcones against antibiotic resistant efflux pump (AcrB) via computational study.

The cases of bacterial multidrug resistance are increasing every year and becoming a serious concern for human health. Multidrug efflux pumps are key players in the formation of antibiotic resistance, which transfer out a broad spectrum of drugs from the cell and convey resistance to the host. Efflux pumps have significantly reduced the efficacy of the previously available antibiotic armory, thereby increasing the frequency of therapeutic failures. In gram-negative bacteria, the AcrAB-TolC efflux pump is the principal transporter of the substrate and plays a major role in the formation of antibiotic resistance. In the current work, advanced computer-aided drug discovery approaches were utilized to find hit molecules from the library of biogenic chalcones against the bacterial AcrB efflux pump. The results of the performed computational studies via molecular docking, drug-likeness prediction, pharmacokinetic profiling, pharmacophore mapping, density functional theory, and molecular dynamics simulation study provided ZINC000004695648, ZINC000014762506, ZINC000014762510, ZINC000095099506, and ZINC000085510993 as stable hit molecules against the AcrB efflux pumps. Identified hits could successfully act against AcrB efflux pumps after optimization as lead molecules.Communicated by Ramaswamy H. Sarma.

Computational Exploration of Anti-cancer Potential of Flavonoids against Cyclin-Dependent Kinase 8: An In Silico Molecular Docking and Dynamic Approach.

Over the centuries, cancer has been considered one of the significant health threats. It holds the position in the list of deadliest diseases over the globe. In women, breast cancer is the most common among many cancers and is the second most common cancer all over the world, while lung cancer is the first. Cyclin-dependent kinase 8 (CDK8) has been identified as a critical oncogenic driver that is found in breast cancer and associated with tumor progression. Flavonoids were virtually screened against CDK8 using molecular docking, drug-likeness, ADMET prediction, and a molecular dynamics (MD) simulation approach to determine the potential flavonoid structure against CDK8. The results indicated that ZINC000005854718 showed the highest negative binding affinity of -10.7 kcal/mol with the targeted protein and passed all the drug-likeness parameters. Performed molecular dynamics simulation showed that docked complex systems have good conformational stability over 100 ns in different temperatures (298, 300, 305, 310, and 320 K). The comparison between calculated binding free energy via MM/PB(GB)SA methods and binding affinity calculated via molecular docking suggested tight binding of ZINC000005854718 with targeted protein. The results concluded that ZINC000005854718 has drug-like properties with tight and stable binding with the targeted protein.

Synthesis and preliminary biological profile of new NO-donor tolbutamide analogues.

We describe a new class of NO-donor hypoglycemic products obtained by joining tolbutamide, a typical hypoglycemic sulfonylurea, with a NO-donor moiety through a hard link. As NO-donors we chose either furoxan (1,2,5-oxadiazole 2-oxide) derivatives or the classical nitrooxy function. A preliminary biological characterization of these compounds, including stimulation of insulin release from cultured rat pancreatic ß-cells and in vitro vasodilator and anti-aggregatory activities, is reported.

Design and in silico investigation of novel Maraviroc analogues as dual inhibition of CCR-5/SARS-CoV-2 Mpro.

A sudden increase in life-threatening COVID-19 infections around the world inflicts global crisis and emotional trauma. In current study two druggable targets, namely SARS-COV-2 Mpro and CCR-5 were selected due to their significant nature in the viral life cycle and cytokine molecular storm respectively. The systematic drug repurposing strategy has been utilized to recognize inhibitory mechanism through extensive in silico investigation of novel Maraviroc analogues as promising inhibitors against SARS-CoV-2 Mpro and CCR-5. The dual inhibition specificity approach implemented in present study using molecular docking, molecular dynamics (MD), principal component analysis (PCA), free energy landscape (FEL) and MM/PBSA binding energy studies. The proposed Maraviroc analogues obtained from in silico investigation could be easily synthesized and constructive in developing significant drug against COVID-19 pandemic, with essentiality of their in vivo/in vitro evaluation to affirm the conclusions of this study. This will further fortify the concept of single drug targeting dual inhibition mechanism for treatment of COVID-19 infection and complications.

Triphenylphosphine Oxide Removal from Reactions: The Role of Solvent and Temperature.

Here, a large-scale feasible, chromatography-free process to purge triphenylphosphine oxide (TPPO) from the crude product of Mitsunobu and Wittig reactions has been developed. Divergence in physicochemical properties like polarity and solubility of TPPO against the product was utilized to precipitate TPPO directly from the reaction mixture and eliminate by simple filtration on a kilogram scale at a pilot plant with high purity of the product.

Synthesis and Biological Evaluation of Novel Benzhydrylpiperazine-Coupled Nitrobenzenesulfonamide Hybrids.

A series of novel benzhydryl piperazine-coupled nitrobenzenesulfonamide hybrids were synthesized with good to excellent yields. They were tested for in vitro inhibition of mycobacterial activity against the Mycobacterium tuberculosis H37Rv strain, in vitro cytotoxicity MTT (RAW 264.7cells) assay, nutrient starvation (H37Rv strain), and ability to block Cav3.2 T-type calcium channels. Novel hybrids did not inhibit T-type calcium channels, whereas they showed excellent antituberculosis (TB) activity and low cytotoxicity with a selectivity index of >30. A direct impact of the amino acid linker was not observed. Studied hybrids exhibited good inhibition activities, and the 2,4-dinitrobenzenesulfonamide group emerged as a promising scaffold for further drug design by hybridization approaches for anti-TB therapy.

Efficient Synthesis of Potential Impurities in Levonadifloxacin (WCK 771).

Levonadifloxacin (WCK 771) is a novel broad-spectrum anti-methicillin-resistant Staphylococcus aureus (MRSA) agent recently launched in India. Five process impurities and one degradation impurity were synthesized as reference standards for their quantification by high-performance liquid chromatography (HPLC) methodology in drug substance and drug product. These compounds are not easily commercially available. The synthesis and characterization of these impurities are discussed in detail.

Potential of NO donor furoxan as SARS-CoV-2 main protease (Mpro) inhibitors: in silico analysis.

The sharp spurt in positive cases of novel coronavirus-19 (SARS-CoV-2) worldwide has created a big threat to human. In view to expedite new drug leads for COVID-19, Main Proteases (Mpro) of novel Coronavirus (SARS-CoV-2) has emerged as a crucial target for this virus. Nitric oxide (NO) inhibits the replication cycle of SARS-CoV. Inhalation of nitric oxide is used in the treatment of severe acute respiratory syndrome. Herein, we evaluated the phenyl furoxan, a well-known exogenous NO donor to identify the possible potent inhibitors through in silico studies such as molecular docking as per target analysis for candidates bound to substrate binding pocket of SARS-COV-2 Mpro. Molecular dynamics (MD) simulations of most stable docked complexes (Mpro-22 and Mpro-26) helped to confirm the notable conformational stability of these docked complexes under dynamic state. Furthermore, Molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) calculations revealed energetic contributions of key residues of Mpro in binding with potent furoxan derivatives 22, 26. In the present study to validate the molecular docking, MD simulation and MM-PBSA results, crystal structure of Mpro bound to experimentally known inhibitor X77 was used as control and the obtained results are presented herein. We envisaged that spiro-isoquinolino-piperidine-furoxan moieties can be used as effective ligand for SARS-CoV-2 Mpro inhibition due to the presence of key isoquinolino-piperidine skeleton with additional NO effect.Communicated by Ramaswamy H. Sarma.

Synthesis and Modeling Studies of Furoxan Coupled Spiro-Isoquinolino Piperidine Derivatives as NO Releasing PDE 5 Inhibitors.

Nitric oxide (NO) is considered to be one of the most important intracellular messengers that play an active role as neurotransmitter in regulation of various cardiovascular physiological and pathological processes. Nitric oxide (NO) is a major factor in penile erectile function. NO exerts a relaxing action on corpus cavernosum and penile arteries by activating smooth muscle soluble guanylate cyclase and increasing the intracellular concentration of cyclic guanosine monophosphate (cGMP). Phophodiesterase (PDE) inhibitors have potential therapeutic applications. NO hybridization has been found to improve and extend the pharmacological properties of the parental compound. The present study describes the synthesis of novel furoxan coupled spiro-isoquinolino-piperidine derivatives and their smooth muscle relaxant activity. The study reveals that, particularly 10d (1.50 ± 0.6) and 10g (1.65 ± 0.7) are moderate PDE 5 inhibitors as compared to Sidenafil (1.43 ± 0.5). The observed effect was explained by molecular modelling studies on phosphodiesterase.

Phytochemical and medicinal importance of Ginkgo biloba L.

Ginkgo biloba L., also popularly known as living fossil, possesses a variety of biological and pharmacological activities. The leaf extract of G. biloba L. (EGb 761) has been used for years to treat age-related memory-deficit problems, including Alzheimer's and dementia. Experimental and clinical studies have revealed its beneficial effects on a wide range of pathological conditions including hepatoprotective, photoprotective effects, DNA repair mechanism, antioxidant and anti-inflammatory activities. Recent studies have also suggested that leaf extract of G. biloba L. may exert beneficial effects on cancer. This review focuses on recent scientific evidence of the reported medicinal effects of G. biloba L.